I. Autoimmune Diseases in General
Autoimmune diseases are caused by an abnormal immune response involving either cells or antibodies directed against normal tissues. A number of strategies have been developed to suppress autoimmune diseases, most notably drugs which nonspecifically suppress the immune response. A method of inducing immunologic tolerance by the oral administration of an antigen to prevent autoimmune responses was first demonstrated by Wells in 1911. Wells, H., J. Infect. Dis. 9:147 (1911). The oral induction of unresponsiveness has also been demonstrated for several T-cell dependent antigens. Ngan, J. et al., J. Immunol. 120:861 (1978), Gautam, S. et al., J. Immunol. 135:2975 (1985), Titus, R. et al., Int. Arch. Allergy Appl. Immun. 65:323 (1981). Antigen-driven peripheral immune tolerance by the oral route has recently been shown to serve as an effective immunoregulatory therapeutic approach in several experimental autoimmune diseases (Higgins, P. J., et al., J. Immunol. 140:440 (1988); Lider, O., et al., J. Immunol. 142:748-752 (1989); Bitar, D. M., et al., Cell. Immunol. 112:364 (1988); Nussenblatt, R. B., et al., J. Immunol. 144:1689 (1990); Nagler-Anderson, C., et al., Proc. Natl. Acad. Sci. U.S.A. 83:7443-7446 (1986); Thompson, H. S. G., et al., Clin. Exp. Immunol. 64:581-586 (1986)).
II. Experimental Allergic Encephalomyelitis
Scientists have also studied ways to suppress autoimmune diseases in various animal models. Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease directed against myelin basic protein (MBP) and has been studied as a model for multiple sclerosis in several mammalian species. See, Alvord, E. et al., Experimental Allergic Encephalomyelitis- A Useful Model For Multiple Sclerosis (Allan R. Liss, New York, 1984). Immunoregulation of EAE is known to be at least partially dependent on suppressor T cells (Ts). It has been shown that Ts are present in rats which have recovered from EAE. Swierkosz, J. et al., J. Immunol. 119:1501 (1977). Furthermore, it has been shown that suppressor T cells account for the unresponsiveness to EAE that is exhibited by some mouse strains. Lando, Z. et al., Nature 287:551 (1980).
Various methods have been employed to induce antigen-specific suppression of EAE. For example, immunization with MBP emulsified in incomplete Freund's adjuvant, as shown by Lando, Z. et al., J. Immunol. 126:1526 (1981), and intravenous injection of MBP-conjugated lymphoid cells as shown by Sriram, S. et al., Cell. Immunol. 75:378 (1983) have been used.
Three papers by Alvord et al. are reported in Annals of Neurology in Vol. 6 at pp. 461-468, 468-473, and 474-482, respectively (1979). The first and second of these papers disclose the suppression of EAE in monkeys by the parenteral administration of MBP only when administered together with a nonspecific adjunctive factor, e.g., an antibiotic or a steroid. The third report discloses the presence in the cerebrospinal fluid of patients with multiple sclerosis of several proteases that degrade MBP to antigenically active peptide fragments.
Papers by Traugott et al., J. Neurological Science 56:65-73 (1982), and Raine et al., Lab. Investigation 48:275-84 (1983) disclose that treatment of a strain of guinea pigs suffering from chronic relapsing EAE by parenterally administered MBP alone or in incomplete Freund's adjuvant (IFA) or in combination with a lipid hapten of myelin, namely, galactocerebroside, suppressed the clinical symptoms of EAE.
Furthermore, McKenna et al., Cell. Immun. 81:391-402 (1983), discloses that preinjection of rats with guinea pig MBP coupled to syngeneic spleen leukocytes or to syngeneic red blood cells suppressed the subsequent induction of EAE using guinea pig MBP in Freund's complete adjuvant. The degree of suppression correlated positively with the amount of MBP administered.
A report by Strejan et al., Cell. Immun. 84:171-184 (1984), discloses that preinjection of rats with guinea pig MBP encapsulated within phosphatidylserine liposomes suppressed the clinical signs and symptoms of EAE that appear in rats injected with guinea pig MBP in complete Freund's adjuvant.
Another paper by McKenna et al., Cell. Immun. 88:251-259 (1984), discloses that the suppressive effects of injected guinea pig MBP leukocyte complexes disclosed in their 1983 report was abolished when animals were pretreated with cyclophosphamide, a drug that inhibits the production of suppressor T lymphocytes.
A report by Krasner et al., Neurology 36:92-94 (1986) discloses that synthetic C copolymer I, which is being tested as a treatment for multiple sclerosis because it protects animals against EAE, does not exhibit immunologic cross-reactivity with MBP.
Additionally, Belik et al., Vopr. Med. Khim. 24:372-377 (1978), discloses the parenteral administration of "alkaline myelin protein fragment" and "synthetic encephalitogenic peptide" to guinea pigs with EAE. The animals recovered after administration of "alkaline myelin protein fragment" to the animals sensitized by bovine "alkaline myelin protein fragment" or by "synthetic encephalitogenic peptide."
Previous studies in EAE and EAU demonstrated that increasing dosages of MBP or S-Ag were associated with better disease protection (Higgins, P. J., et al., J. Immunol. 140:440 (1988); Nussenblatt, R. B., et al., J. Immunol. 144:1689 (1990)) and, in general, investigators have reported enhancement of oral tolerance by feeding larger amounts of antigen (Mowat, A. M., Immunol. Today 8:93 (1987)).
One report has suggested that EAE may be suppressed by adoptive transfer of CD8.sup.+ T cells from orally tolerized animals (Lider, O., et al., J. Immunol. 142:748-752 (1989)).
However, it is not known in the art to successfully treat EAE after EAE manifests itself in the afflicted animal. Also, it is not known in the art to successfully treat multiple sclerosis after multiple sclerosis manifests itself in the patient. Thus a need still exists for a method of suppressing and treating multiple sclerosis.
III. Adjuvant Arthritis
Adjuvant arthritis (AA) is an experimental model of inflammatory joint disease and especially a model of rheumatoid arthritis. Adjuvant arthritis is induced by intradermal injection of a suspension of Mycobacterium tuberculosis (MT) in oil (Pearson, C. M., J. Chronic Dis. 16:863-874 (1963)). Between 10 and 15 days following injection, animals develop a severe, progressive arthritis.
Because of its resemblance to human rheumatoid arthritis in both clinical and histopathological features (Jasin, H. E., Federation Proc. 32:147 (1972)), AA has been used as a model to investigate mechanisms of immune mediated joint disease and to investigate methods for the treatment of an organ specific autoimmune disease.
Adjuvant arthritis is a cell mediated autoimmune disease and can be transferred by cell populations or by T cell clones specific for MT (Taurog, J. D. et al., Cell. Immunol. 75:271 (1983); Taurog, J. D. et al., Cell. Immunol. 80:198 (1983); Cohen, L. R. et al., Arthritis and Rhem. 28:841 (1985)). Studies have suggested that the primary autoantigen in adjuvant arthritis is a 65-kd mycobacterial heat shock protein (HSP) (van Eden, W. et al., Nature 331:171 (1988)). This protein also appears to be important in streptococcal cell wall arthritis (DeJoy, S. Q. et al., J. Exp. Med. 170:369 (1989); van den Broek, M. et al., J. Exp. Med. 170:449 (1989)). Immunity to type II collagen has been shown to exist in adjuvant arthritis (Trentham, D. E. et al., J. Clin. Invest. 66:1109 (1980)).
Tolerization following oral and intravenous administration of collagen has been shown to suppress another type of arthritis termed collagen-induced arthritis (CIA). Suppression of CIA in DBA mice by orally administered type II collagens (CII) is dose-dependent with suppression observed when 0.5 mg but not 3 mg was given 8 times over a two-week period (Nagler-Anderson, C., et al., Proc. Natl. Acad. Sci. U.S.A. 83:7443-7446 (1986)). Similar results were reported for CIA in rats with greater protection when CII was given at 2.5 .mu.g/g than 25 .mu.g/g (Thompson, H. S. G., et al., Clin. Exp. Immunol. 64:581-586 (1986)). In terms of i.v. tolerization, 1 mg was given to suppress CIA in DBA mice (Myers, L. K., et al., J. Exp. Med. 170:1999 (1989)).
Adoptive transfer of protection for CIA arthritis has been reported for animals treated intravenously with CII (Myers, L. K., et al., J. Immunol. 143:3976 (1989)) but not for oral tolerization (Nagler-Anderson, C., et al., Proc. Natl. Acad. Sci. U.S.A. 83:7443-7446 (1986); Thompson, H. S. G., et al., Clin. Exp. Immunol. 64:581-586 (1986)).
However, it has not previously been known that oral administration of CII suppresses AA, the animal model for human rheumatoid arthritis, and that this suppression can be adoptively transferred by splenic T cells from CII fed animals.
Thus a need exists for the treatment of autoimmune diseases, and especially for the treatment of T cell-mediated or T cell-dependent autoimmune disease.